Lewy body diseases (LBDs) are characterized by degeneration of the dopaminergic system, motor alterations, cognitive impairment, and formation of Lewy bodies (LBs) (see, e.g., McKeith et al, Neurology 1996, 47:1113-1124). LBDs include Parkinson's disease (PD), Diffuse Lewy body disease (DLBD), Lewy body variant of Alzheimer's disease (LBV), combined Parkinson's disease (PD) and Alzheimer's disease (AD), as well as the syndromes identified as multiple system atrophy (MSA). Dementia with Lewy bodies (DLB) is a term coined to reconcile differences in the terminology of LBDs. Disorders with LBs continue to be a common cause for movement disorders and cognitive deterioration in the aging population (see e.g., Galasko et al., Arch. Neurol. 1994, 51:888-895).
In recent years, new hope for understanding the pathogenesis of LBDs has emerged. Several studies suggest that the synaptic protein alpha-synuclein plays a central role in PD pathogenesis. For example, alpha-synuclein accumulates in LBs (see e.g., Spillantini et al., Nature 1997, 388:839-840; Takeda et al., J. Pathol. 1998, 152:367-372; and Wakabayashi et al., Neurosci. Lett. 1997, 239:45-48). Further, mutations in the alpha-synuclein gene co-segregate with rare familial forms of parkinsonism (see e.g., Kruger et al., Nature Gen. 1998, 18:106-8; and Polymeropoulos, et al., Science 1997, 276:2045-2047). In addition, overexpression of alpha-synuclein in transgenic mice (e.g., Masliah et al., Science 2000, 287:1265-1269) and Drosophila (see e.g., Feany et al, Nature 2000, 404:394-398) mimics several pathological aspects of PD.
Many scientists believe that PD is a relatively late development in a systemic synucleinopathy and that “parkinsonism is just the tip of the iceberg” (Langston, Annals of Neurology (2006) 59:591-596). For example, Lewy bodies have been described in sympathetic ganglia and in the myenteric plexus of the gut (Herzog E., Dtch Z Nervenheilk (1928) 107:75-80; Kupsky et al., Neurology (1987) 37:1253-1255). Various disorders have been associated with the presence of Lewy bodies. For example, Lewy bodies have been found in the brain stem of a patient with rapid eye movement sleep behavioral disorder (Uchiyama et al., Neurology (1995) 45:709-712). Olfactory dysfunction has been reported in many PD patients long before the development of parkinsonism. Examination of cardiac tissue from patients with incidental Lewy body disease and typical PD revealed synuclein-positive neuritis in the myocardium (Iwanaga et al., Neurology (1999) 52:1269-1271). There is also evidence that esophageal, lower bowel and bladder dysfunction are early manifestations of PD-related pathology in the peripheral autonomic system (Qualman et al., Gastroenterology (1984) 87:848-856; Castell et al., Neurogasdtroenterol Motil (2001) 13:361-364; Hague et al., Acta Neuropathol (Berl) (1997) 94:192-196). Thus, the fact that accumulation of alpha-synuclein in the brain and other tissues is associated with similar morphological and neurological alterations in species as diverse as humans, mice, and flies suggests that this molecule contributes to the development of PD.
Although the incidence of LBDs continues to increase, creating a serious public health problem, these disorders lack approved treatments.